Annexin A1 Tripeptide Mimetic Increases Sirtuin-3 and Augments Mitochondrial Function to Limit Ischemic Kidney Injury

Frontiers in Physiology

Jamie R. Privratsky¹  Qing Ma¹  Benjamin T. Morris¹  Hagir Suliman¹  Zhiquan Zhang¹  Luis Ulloa¹  Jiafa Ren²  Steven D. Crowley³ 

[1] Center for Perioperative Organ Protection, Department of Anesthesiology. Duke University Medical Center, Durham, NC, United States;Department of Medicine, Duke University Medical Center, Durham, NC, United States;Department of Medicine, Durham VA Medical Center, Durham, NC, United States;

关键词: acute kidney injury;    mitochondrial integrity;    sirtuin 3;    ischemia/reperfusion injury;    mitochondria;   

DOI  :  10.3389/fphys.2021.683098

来源: DOAJ

【 摘 要 】

Background: Acute kidney injury (AKI) is one of the most common organ failures following surgery. We have developed a tripeptide mimetic (ANXA1sp) of the parent annexin A1 molecule that shows promise as an organ protectant limiting cellular stress; however, its potential as a kidney protective agent remains unexplored, and its mechanism of action is poorly understood. Our hypothesis was that ANXA1sp would limit kidney injury following surgical ischemic kidney injury.Methods: In a blinded fashion, wildtype mice were assigned to receive vehicle control or ANXA1sp one hour prior to and one hour after kidney vascular clamping. Our primary outcomes were markers of kidney injury and function as measured by serum creatinine and histologic injury scoring of kidney tissue sections. Immunofluorescence microscopy, real-time PCR, and Western blot were used to assess cell death, oxidative stress, and mitochondrial biomarkers. An in vitro model of oxygen-glucose deprivation in immortalized kidney tubule cells was used.Results: ANXA1sp given prior to and after ischemic kidney injury abrogated ischemic kidney injury. ANXA1sp limited cell death both in vivo and in vitro and abrogated oxidative stress following ischemia. ANXA1sp significantly increased the expression of markers associated with protective mitophagy and limited the expression of markers associated with detrimental mitochondrial fission. ANXA1sp upregulated the expression of the mitochondrial protectant sirtuin-3 (SIRT3) in the mitochondria of kidney tubular cells. Silencing of SIRT3 reversed ANXA1sp-mediated protection against hypoxic cell death.Conclusions: ANXA1sp limits kidney injury, upregulates SIRT3, and preserves mitochondrial integrity following ischemic kidney injury. ANXA1sp holds considerable promise as a perioperative kidney protectant prior to ischemia inducing surgery and kidney transplantation.

【 授权许可】

Unknown